Cardiovascular disease (CVD) is projected to remain the #1 killer this century worldwide. Key CVD risk factors, such as type 2 diabetes and obesity, have reached epidemic proportions, even among younger adults. Sex hormones (such as estrogen and testosterone) are centrally involved in progression to CVD in both men and women. Men are at especially high risk for CVD: male gender confers a 3-fold increased risk of CVD and CVD death rates are shifted 5-10 years earlier in men than in women. The standard explanation for the differing CVD risk invokes differing amounts of endogenous estrogen: greater endogenous estrogen in women, relative to men, provides CV protection until menopause. However, evidence is accumulating that the estrogen explanation is an over-simplification. Our general objective is to identify the roles of the "other" endogenous sex hormones (estrogen in men and androgen in women), in relation to glucose dysregulation, in the development CVD across the adult lifespan. Towards this goal, we propose to relate endogenous sex hormones, glucose dysregulation, and CVD in older adults and relate endogenous sex hormones to atherosclerosis and cardiac dysfunction in younger adults. Our approach centers on two emerging concepts: endogenous sex hormones may assert opposite (or gender-dimorphic) effects in men compared with women and temporal changes, not just levels, of endogenous sex hormones influence CVD risk. We propose to take an efficient, endocrine epidemiological approach. We will use existing data and measure endogenous sex hormones in banked blood already collected repeatedly from Native American men and women within two ongoing longitudinal studies, the Strong Heart Study and the Strong Heart Family Study. Native Americans are a minority group with high rates of CVD and diabetes. Our specific aims are: 1) to differentiate if change in circulating endogenous estrogen, androgen, and SHBG are associated with subsequent CVD events in men and women with diabetes;2) to determine if levels of circulating endogenous estrogen, androgen, and sex hormone binding globulin (SHBG) levels are associated with subsequent pre-diabetes and diabetes;and 3) across the adult lifespan in men and women, to characterize endogenous androgen and estrogen dynamics and their relationships to carotid atherosclerosis, cardiac dysfunction, and related risk factors, particularly glucose dysregulation and obesity. A better understanding of the interplay of sex hormones and CVD and its risk factors during aging would broadly impact public health strategies, risk stratification, and treatment of CVD. PUBLIC HEALTH RELEVANCE: Cardiovascular disease (CVD) is the #1 killer worldwide. Elders carry the greatest CVD burden, but atherosclerosis and CV dysfunction is rising rapidly in younger adults, especially among Native Americans. This study seeks to enhance significantly our understanding of how sex hormones (such as estrogen and testosterone) influence glucose dysregulation and CVD risk, in young to elder men and women. Millions of men and women are taking sex hormone therapies for a variety of health problems. The study seeks to identify who might benefit (and who might be harmed) from such therapies and to formulate sex hormone-altering therapies seeking to reduce CVD incidence and severity.